Diabetic patients have an increased risk of developing atherosclerosis and its complications compared with non-diabetic individuals, and individuals with atherosclerosis frequently have type 2 diabetes mellitus (T2DM). Both diseases have a strong genetic component and show familial clustering. A critical unsolved question is whether there are genetic connections between common forms of atherosclerosis and T2DM? We have found that apolipoprotein E-deficient (Apoe-/-) mice on the C57BL/6 (B6) background develop T2DM when fed a Western diet. In contrast, atherosclerosis- resistant BALB/c (BALB) Apoe-/- mice are resistant to it. We performed quantitative trait locus (QTL) analysis on an intercross derived from B6.Apoe-/- and BALB.Apoe-/- mice and found that the QTL for atherosclerosis coincided with the QTL for hyperglycemia in the middle portion of chromosome 5. In Aim 1, we will conduct fine mapping for this region by making congenic strains. Speed-congenic lines will be generated by introducing the chromosome 5 region harboring the QTLs from BALB.Apoe-/- into B6.Apoe-/- mice, and the resultant congenic strains will be analyzed for genetic effects on atherosclerosis and T2DM development. Subcongenic strains will be constructed to determine whether atherosclerosis and hyperglycemia are controlled by the same causal gene or two linked but unique genes in the region. In Aim 2, we will conduct functional study to test Hnf1a as a promising candidate gene for the chromosome 5 QTLs. Polymorphisms in the Hnf1a locus are associated with coronary heart disease and T2DM risk in humans. There are multiple SNPs within the Hnf1a gene between B6 and BALB with one SNP in exon 9 leading to amino acid substitution. Recent genome- wide association studies have identified new loci that are implicated in -cell development and function, highlighting insulin secretion in the development of T2DM in humans. B6.Apoe-/- mice exhibit significant defects in cell function but have no significant defects in insulin sensitivity. Significant macrophage infiltration in the islets has been observed when T2DM occurs in these animals. In Aim 3, we will use this unique model to investigate whether inhibition of islet inflammation would prevent diabetes and ameliorate atherosclerosis in B6.Apoe-/- mice. Taken together, this work will uncover genetic connections between the two important diseases.